Synthesis of 4-hydroxycoumarins



Patened May 24, 1949 The present applicationhsYa'divsioniiof:nur

-zooera'clngapplication'. Seriali Noal1456f110, filed Ourzinventionrelates tez-the Synthesisof ehyf' droxycoumaiin and l\-hydrocarbonsubstituted- 'iignalapplicati@ August :29, 456310.k Dividea vmui this apuary 21, 1947, Serial No. 730,206

yields.,` is more:'.convenientfrfriom anmanipulabive rstandp'oint, and vis`suitalole fonlargef-soal'e puoduetion; J and! t'oLpuriythemsimply fahdireffeotvely.

These 4-l1ydroxycoumarns are desmotropc, `-sind 'have both rlthe. Aemolcstifucture-rimlieatel by -thatf name 1 and .Jthe lrlcetof structure: yin'dicatzecl by :.the linfime 2,4rdiketoehromans. They are represented 'by Y,the following ffgen'eal lforifmila:

' 'Enolorm "Keto-'form in 'which R. represents 2A).A member off-.,-izlje {elss consisting. Oi hydrogen, and I monvallent: hyd-roshow only the enol forms, and shall u's'elx'il'yhe 'vn'anife Ll"-'l'iydroxyeounfiarins; 'alndi'n formulas .shall Serin, Berichte, v0.17. 50, p.'.'12'9 2 (1917i, Y @sauer and Schoder, ArchPharm., Win59, p:53 1929).

4l y' 5 Phenylacetylsalicylic acid yl ester meth esses without a solvent, by adding metallic sodium to molten acetylsalieylic acid methyl ester or to molten phenylacetylsalicylic acid methyl ester. They point out that in doing this the reaction temperature must be kept within the deiinite and narrow range or" i60-175 C.; for reaction does not occur appreciably below about 160 C., and under their conditions overheating (leading ultimately to carbonization) occurs if the temperature rises above about 175 C. Since the reaction evolves much heat, this means that the sodium must be added very slowly, and in very small pieces, and invoives a careful and diflicult temperature control-a temperature control which is especially difficult, if not impossible at points, because of the local Superheating produced at and near the metallic sodium, even if this is added in small particles. particles frequently ignite the vapors produced.

Moreover, as the Pauly and Lockemann reaction progresses, the reaction mixture becomes thick and viscous (which makes stirring and hence intimate mixing very diflicult), and finally solidies in a mass-in the reaction vessel itself unless extreme care is taken. Because of these things, the Pauly and Lockemann reaction must be carried out in very small batches, of about 100 grams as a maximum; even with those small batches stirring and temperature control are Very difficult, and with larger batches effective stirring and temperature control are practically impassible.

In addition, the Pauly and Lockemann reaction between metallic sodium and the initial molten ester, with no solvent, is accompanied by many side reactions; and their method oi recovery, which requires many recrystallizations and necessitates the handling of large quantities oi hot solutions and the consequent labor in manipulation and loss in yield, does not readily and effectively separate the desired l-hydroxycoumarin from the products of these side reactions. Ilhese things make very diilcult the obtaining of a 4-hydroxycoumarin of reasonable purity; and make substantially impossible the obtaining of eiective yields. While Pauly and Lockemann reported that their yield was 55%, We have been unable in many repeatings of their process to get a yield of over l2-l4% of any 4-hydroxycoumarin of reasonable purity-although We have obtained I' much larger amounts of various unwanted acidic lay-products, which Pauly and Lockemann perhaps included in their 55%.

We have discovered the surprising fact that we can largely or wholly avoid these difculties, and can about double the yield over the best we can obtain by the Pauly and Lockemann procedure, by carrying out the reaction in an inert solvent, most effectively at a higher temperature than is possible when no solvent is used.

By using an inert solvent, we get many advantages:

1. The temperature may be accurately and easily controlled.

2. The stirring may be easily and effectively done.

3. The danger of solidiflcation of the reaction mixture is avoided.

4. The 4-hydroxycoumarins are obtained (as sodium salts) in a form readily collectible by ltering or decanting and better adapted for further operations-such (a) as purification, and (b) as further reaction if the 4-hydroxycoumarin is to be used as an intermediate. In some cases, notably Ll-hydroxycoumarin itself,

rihe hot sodium i this form is a ne powder, instead of the solid mass which Pauly and Lockemann obtained.

5. The permissible temperature range is broader, and extends higher, with the optimum temperature considerably higher than the 175 uppel` limit of Pauly and Lockemann. In the 16C-175 range the reaction product is nearly half salicylic acid; but by raising the temperature, as `our process permits but the Pauly and Lockemann process does not permit, the amount of salicyclic acid in the reaction product is decreased, to substantially zero at about 220-230 C., and the yield of the Ll-hydroxycoumarin is increased. With our process the maximum yield of 4-hydroxycoumarin is with the temperature between 220 and 280 C.

6. The 4-hydroxycoumarins obtained are purer, and purication is easier, especially when the reaction temperature is in the optimum range of 220280 C.; and in consequence fewer recrystallizations are necessary.

7. The order of adding reactants is immaterial.

8. The ratio of reactants is not critical; for the sodium may be present in considerable excess, and .may be as low as 60% of theory, without materially affecting the reaction or the yield.

9. According to the invention contemplated in the present application, the alkali metal which serves as the condensing agent in the reaction of Equation 2 is present in metallic form.

10. It is unnecessary to use initial reactants of high purity.

Many different inert solvents may be used. In fact, any solvent may be used which has at least a portion in liquid phase (even if it is boiling) at the reaction temperature and with which the initial acyl salicylic acid ester and the alkali metal and the final fl-hydroxycoumarin do not react.

Among the inert solvents which can be used are those high-boiling hydrocarbons and petroleum fractions of which at least part remains in liquid phase at the temperature used in the reaction. These include parailns and other hydrocarbons, kerosene, fuel oils, and lubricating oils. A high-boiling ether not subject to cleavage in the presence of sodium at high temperatures can also be used as the inert solvent, one such ether being the dimethyl ether of tetraethyleneglycol, known as dimethoxytetragiycol.

The solvent which we prefer is a high-boiling paraffin fraction liquid at about C. or lower and boiling at not less than 260 C. One such high boiling paraffin fraction, which we have found very suitable, is sold by the Standard Oil Company of Indiana under the trade-mark Stanolind We have also discovered that we can simply and effectively purify 4-hydroxycoumarins by forming a water solution of an alkali-metal salt of the impure i-hydroxycoumarin, adding acid to lower the pH to a value low enough to produce a precipitate containing impurities but high enough to avoid material precipitation of the /l-hydroxycoumarin, removing the precipitate so produced, and then adding more acid to the remaining aqueous phase to lower the pH to a value low enough to precipitate the 4-hydroxycoumarin in purified form. These pH values vary with different ll-hydroxycoumarins The rst is slightly above the pK value for the particular 4-hydroxycoumarin, say by about one pH unit; and the second is definitely below that pK value, and conveniently well below it by the use of an excess of acid. They may be determined by plotting the aat-1,04%

ple --of -1 the aqueoussolution of f' the alkali-metal f salteisprogressively acid-ulated, and keeping the firstL pI-I-E value somewhat vabove and thesecond well below the lplateau which the curve shows.

The Vfollowing are wexamples offoureprocess:

Example 11.-.4-hydroycoumainr Au. Preparing. acetylmethylsalicylate.-To prepare.4-hydroxycoumarin we. use acetylmethylsalicylate. (acetylsalicylic acid` methyl ester) as a.reactant.v: If this. isnotfavailable, it may be preparedl as follows: To.` a. mixture of 2 kg. of methylsalicylate and 12kg.; oil acetic. anhydride addzleml.: oiaconcentrated sulfuric yacid and mix thoroughly. Then.,allow.the..mixture:to stand .at Y,

about room temperature about 40 minutes, and then add the mixture slowly to about l liters of cold water; which desirably contains a liberal amount of seed crystals (ifavailable) from a previous :run and should be well stirred during the addition and forsome time afterwards, say about half an hour. Allow the resultant mixture to stand about six, hours to decompose the excess acetic anhydride, and then recoverthe solidmaterialvibydltration andwash it with water. It is the` desired acetylmethylsalicylate; and has a melting pointofabout 4'7-49 C. without recrystallization. The yieldfis about 2350 grams (92% of theory) about 1200 ml. of ahigh-boiling `petroleum fraction (St anolind) and 96 grams (4.1 moles) of sodium in a suitable ask, conveniently equipped with-.a stiff stirrer (such as a Hersberg vstirrer),

a, thermometer, a short fractionation column with oondenserand receiver, and an introduction port.

Heat this lto .about 2402250? C., conveniently on-y a metal bath; and then, withthestirrer operating, slowly add 800 grams (4.1 moles) of dry aetylmethylsalicylate, desirably in small portions, over a period of -about thirty minutes. If desiredLthe order of additionmay be reversed; with.t1je acetylmothylsalicylate added first and the sodium later; but -we fndit more convenient to add thesodium first.

After thegaddition ofl reactants is completed,

about 90; minutes. The temperature named (240?'-250 C.) may be varied considerably; from as low as 180'C;, or even 160 C although that things.) As the reaction thencontinues, a brown.

granular productforms.. Thereaction isccmplete, usually in about 90 minutes after the addie tion of acetylmethylsalicylate, when there appearsto be -no metallic sodium in the reaction mixture; whichfmayfbe-tested by removinga small-r sample of suchmixture,I adding ethanol to it, and

getting no evolution ofehydrogen.. When thev reaction is thus determined to be complete the brown product is recovered by filtration, desirably while ItheI-solutioniishot;i The'iproduct so recovered, after being cooledis.washed withg a petroleum fraction, desirably-l a lowfboiling one;`

and ,f any residual, washing liquidis removedby drying. This -brown granular pIfOduct ,islargely the crude sodiumsalt ofifh,ydroxycoumarin;l

formed by the followingvreaction:

Add this brown granular product slowly to about 4 liters of water, desirably maintained at about 60g-'70 C. During thisaddition` the `water should be stirredvigorously, and an-air stream' is desirably blown-overthesurface of the .Water to remove hydrogen and 'to Vquench any smallsodium res that-may lforno if anyv particlesoffunreacted sodium remain.

takes about 30 minutes, add an acid,conveniently concentrated hydrochloric or sulfuric a-cid,finsui cient amount to :reduce thepI-I to about 5.5,.to.

6.0; and maintain the temperature at-about V50 C. During this acidilication,aprecipitate (ofthe l impurities) forms; andai/,about pH,5. 5A-,6.0 this precipitate flocculate's into a lightgllm'my, 4Sticky;y Remove f this, as far aspcssible, byskinnning, and discard itz. Shake out the remaining solution, once with:l a@ suitable impurity-removing lsolvent, most coul/eng..

mass which rises to thefsurface.l

iently an equal volume of ethyl ether but permissibly other oil-solvents such as chloroform or light petroleum fractions,` to remove any: residuum of this gummy precipitate.

Now separate the aqueous phase, and hir-ther-v` acidifyit to about pH 1.5, convenientlyv with hydrochloric or sulfuric acid. During and following this latter acidification the 4-hydroxycoumarin separates'v out, as -a powdery precipitate. To ensure maximum separationl now allow-the whole to stand for several hours, and then collect theprecipitated crude 4-hydroxycoumarin, as by filtration.

While this crude 4`hydroxycournarin is --fairly pure, and sufficiently pure for use, increased purity may be obtained by one ortwo recrystallizations from boiling Water. Residual traces of oily impurities, as those from the petroleum frac tions used, may be removed by filtering the hot aqueous solution of crude 4-'hydroxycoumarin through a heated fluted funnel duringlthe recrystallization.

Additional 4-hydroxycoumarinmay be recovered, in the form of 3,3'fmethylenebis(4hy droxycoumarin) by precipitation from the various mother liquors by the addition of formaldef hyde.

The 4-hydroxycoumarin produced by our proc ess, after one recrystallization, usually .basa

melting point of about-200206 C. Byfrepeated.,`

recrystalli'zations the melting' point may be -increased to 21,3"-217'C.v

The yield of 4-hydroxycoumarin direct is aboutmethylenebis(4-hydroxycoumarin) is about 4-5 l g., which whencalculated -to 4=hydroxycoumarinis another 0.4% to make A the -ftotal yield '-'about'a When alltheA brown` product has been Wellstirred into and foi-the-Y most part dissolved inthe water, which usuallyY 7 Example 2.-4-hydroxycoamarin Example 1 is repeated, except that instead of using acetylmethylsalicylate (the methyl ester of acetylsalicylc acid) We use acetylethylsalicyiate or acetylpropylsalicylate or acetylphenylsalcylate (respectively the ethyl, propyi, and phenyl esters of acetylsalicylic acid) or other convenient alkyl or aryl ester oi acetylsalicylic acid. We obtain 4-hydroxycoumarin in the same way as in Example 1; but the alcohol eliminated in the reaction is ethyl or propyl or phenyl or other alcohol, corresponding to the esterifying group R of the initial acetylsalicylic acid ester.

However, we have found no advantage in the use of the higher esters instead oi the methyl ester of acetylsalicylic acid.

Example 3 4 hyaroycoamarzn Examples 1 and 2 are repeated, except that instead of using one mole of sodium per mole of acetylmethylsalicylate (or other ester) we vary the molecular proportions, with the sodium ranging from 0.6 mole to 2.0 moles per mole of the ester of acetylsalicylic acid. The ratio we prefer is about 0.8 mole of sodium per mole of the ester.

Example 4.-4-hydromycoamarin Examples 1, 2, and 3 are repeated, except that instead of using sodium as the alkali metal we use potassium or lithium. When lithium is used we nd that the optimum reaction temperature is somewhat higher, and when potassium is used we iind that the optimum reaction temperature is somewhat lower, than when sodium is used; it is of the order of 180210 C. for potassium. But we prefer sodium to either potassium or lithium.

Example 5,-3-methyl-4-hydrozrycoamarm A. Preparing prop'ionylmethylsalicylate. To prepare 3-methyl-4-hydroxycoumarin we use propionylmethylsalicylate (propionylsalicylic acid methyl ester) as a reactant. This may be prepared as follows: Mix thoroughly 175 g. oi methyl salicylate, 225 g. of propionic anhydride, and 5 ml. oi concentrated sulfuric acid. Let the mixture stand for about 40 minutes, and then pour it into about 6 liters of water. An oil separates. Wash that oil with sodium-carbonate solution; and then distill it, and collect the fraction which boils at 140144 C. at 15 mm. pressure. This is the desired propionylmethylsalicylate. l e yield is about 218 g. (90%). 1i desired, it be purified by fractional distillation; after which it boils at 14l.5-142 C. at 9 nim. pressure.

D 1.1579; ND25 1.5039.

Analysis: Calculated for CiiHlzCi: C, 63.46; H, 5.79. Found: C, 63.47; H, 5.00.

B. Preparing 3-methyl-4-hydroycoamarin.- To 150 ml. of a suitable mineral oil or other ,inert solvent add about 8.5 g. of sodium, heat to about 250 C., and then slowly of proI pionylmethylsalicylate While stirring vigorously. Maintain the temperature for about minutes, under reflux. Filter o the mineral oil, which leaves behind a powdery residue. Wash that powdery residue with a low-boiling petroleum fraction, and then stir it into and so far as possible dissolve it in about 800 ml. of water. Then acidify the solution, as with hydrochloric or sulfurie acid, to about pH 6.5; whereupon a gummy precipitate forms, which is removed by extraction with ethyl ether or other suitable solvent, such as light petroleum fraction or chloroform. After that gummy precipitate has been thus removed, acidify the remaining aqueous layer to about pH 1.5, as with more hydrochloric or suliuric acid. The desired 3-methyl-4-hydroxycoumarin crystallizes out during this last acidihcatlon. The yield is about 18 g. (28%). After being recrystallized from hot alcohol to which water is added to the point of turbidity, its melting point is about 227228 C. This is very close to the melting point reported by Heilbron and Hill (Jour. Chem. Soc. for 1927, page 1705), for the 3-methyl-4-hydroxycoumarin prepared by them from the acid chloride of acetylsalicylc acid and the diethylester of sodio-methyl-malonic acid--a method wholly different from ours.

Our overall reaction for producing 3-methyl- 4-hydroxycoumarin is as follows:

acid methyl ester Example 6.-3-ethyZ-4-hydroycoumarin A. Preparing n-batyrylmeihylsalicylaie-To prepare S-ethyl-l-hydroxycoumarin we use nbutyrylrnethylsalicylate (n-butyrylsalicylic acid methyl ester) as a reactant. This is prepared as follows: Reflux 106 g. of n-butyryl chloride and 144 g. of methyl salicylate for about one hour. Then distill the mixture, and collect the fraction boiling at -152 C. at 10 mm. pressure. This is the desired n-butyrylmethylsalicylate. The yield is about 170 g. (81%). If desired it may be purified by fractional distillation, after which it boils at -156 C. at 12 mm. pressure.

D25 1.1279; ND25 1.5011.

Analysis: Calculated for C12H14O4: C, 64.86; H, 6.30. Found: C, 64.85; H, 6.42.

B. Preparing the 3-cthyl-4-hydroxycouma- 7'z`n.-To about 105 ml. oi a suitable mineral oil (or other inert solvent) add about 5.2 g. of scdium, heat to about 250 C., and then slowly add about 50 g. of nbutyrylmethylsalicylate, while stirring vigorously. Maintain the temperature, under reux, for about 30 minutes after the addition is complete. Decant oil the mineral oil from the residue, which is guinmy in character; and wash that residue with a low boiling petroleum fraction, and then stir it into and so far as possible dissolve it in about 600 m1. of water. Then acidify the solution to about pH 6.0, as with hydrochloric acid; which produces a gummy precipitate. Extract that gummy precipitate with ethyl ether, chloroform, or light petroleum fraction. Separate the remaining aqueous layer, and acidify it to about pH 1.5. The desired 3- ethyl-4-hydroxycoumarin crystallizes out during this latter acidification. The yield is about 12.0 g. (28%). When recrystallized from ethyl alcohol and water, the melting point is about 155-156 C.

Analysis: Calculated for CiiHioOa: C, 69.47; H, 5.26. Found: C, 69.59; H, 5.41.

Our overall reaction is as follows:

ll-hydroxycoumarin annota Examplel 7;-31-71i-propyl--hyaroycoamarinf.

A; Preparing noalerylmethylsalicylaiaTo prepare 3-n-propyl-4-hydroxycoumarin We use n-valerylmethylsalicylate (n-valerylsalicylic acid methyl ester) as a reactant. It may be prepared as follows: Reflux 50g; of valerie acid and 92 g. of thionyl chloride for about. 4 hours, then. add' 74.5 g. of methylsalicylate, then` reflux for about 3Y hoursY longer, and then fractionally distill. Collect the fraction boiling between. 155 and 160" C. atA 8 mm. pressure. This is the desiredL n'valerylmethylsalicylate. about 75g. (65%).

158:5'-159 C; at 8 mm. pressure.

D 1.1014; ND25 1.4964;

Analysis: Calculated for C13H1SO4VC, 66.10; H, 6.78; Found: C, 66.31; H, 6.90.

B. Preparing 3 rL-propyl 4 hydroyco'ama'- riva-HeatV about 4.9 g; of sodium in 100 ml. of mineral oil (Stanolind) to about 250 C., and slowlyv add 50 g. of n-valerylmethylsalicylate, While stirring vigorously. After the addition maintain the-temperature atabout 250 C., under reflux, for about 'minutes. Then decant the mineral' oil from thev gumrnyresidue which has formed, wash that gummy residue with a lowb'oiling petroleum fraction, and then stirit into and so far as,possib1e dissolve it in about 600 ml; ofwater. Then acidifythe solution toabout pHfG, Whch'causes a gummy precipitate to form; and remove that gummy precipitate, as by eX- tra'ctingwith ether. Separate the aqueous layer, and acidify it to about pH 1.5. The desiredl 3'- n-propyl -4- hydroxycoumarin crystallizes out dur-ing this last acidiiication. The yield is about 13:9-1g. (32%). When the product is recrystallized from ethyl alcohol and Water its melting point is 134135 C.

Analysis: Calculated for Cul-11203: C, 70.759; H, 5.88. Found: C, 70.44; H, 6.09.

Our overall reaction-is as follows:

o (Il \o-oH, Na

O/-oHT-CHZ-om-CH, 25090' A; Preparing isovaleryZmethyZsaZicyZate.-To

prepare 3-isopropyl-4hydroXycoumarin, We use isovalerylmethylsalicylate (isovalerylsalicylic acid methyl ester) as a reactant. It maybe-prepared as= follows: Reflux 100 g. of isova'leric acid and" 18.5` g..of thionyl chloride for. about 2 hours, then. add 149`` g. of .methyl salicylate, then reflux fur-` ther'for about2'hours; and then iractionally. disA till.` Collect the fraction boiling between 145 and.. 154 C. at 8. mm..pressure. sired isoValerylmethylsalicylate.

151=151.5?-C. atSmm'. pressure'.

D25 1.0980; Nb25 1.4960.

Analysis: Calculated for Cisl-11604: C, 66210;`

The yield. is If desired it may be puriiedJ by fractional distillation', after which. it boils at.'

Thisy is thevde Thev yieldl is' about 166 g. (71%).v Ifdesired it may be puried by-'ractional distillation', after which'A it boils .at`

. extraction4 with ether.

Blz Brepari'ria -isopropyl 4y Yhydroxycoamaria-Heat 4.9 g. of sodium in ml. ofV minerali oil to about250' C., then slowly add 50` g. ofiso- Valerylmethylsalicylate WhileL vigorously stirring, and maintain vthetemperatureA of 250 C., under reflux, for about 40 minutes after the additionis. complete. Decant the mineral oil from the gummy residue which has been formed; and" then Wash that gummy residue With a 10W-boiling petroleumV fraction, and. stir. it into and so faras possible dissolve it in about 800 ml. of water. Acidify the solution thus formed to about pH 6.5, as with hydrochloric acid; Which .forms a gummy precipitate. Remove this gummy precipitate by Then separate the aqueous-phase, and acidify it to vpH 1.5, as with hydrochloric acid. The desired 3-isopropyl-4i-hydroxycoumarin crystallizes out during thislast acidication. The yield' is about 11.1 g. (25%). When recrystallzedr fromv ethyl` alcohol and Water, its

melting point isx1724-174" C'.

Analysis-f: Calculatedf for C1'2H'12O3: C; 70;59";t 5.88. FoundC, 71.15.; H', 6:01.

@ur overall reaction is as follows:

Example 9;-3#whaha-4-hydromycoumarin A.Prepar.ingv n: caproriyZmethylsalicylate.-- To. prepa-re. 3Fnfbutyl-4-hydroxycoumarin.We use. capronylmethylsalicylate (capronylsalicylic. acid'- methylester.) as areactant. asffollows.: Reflux. 400. g..of caproic acid and 4924-` g.` of.. thionyl. chloridefor about. 1.0 hours,.then,= add. 67.8:gof methylsalicylate andireflux for about 3,hours longenendthen fractionally distill. Colllect the fraction.boilingbetween165-17090. at 15.l mm. pressure. This is. the desired. capronylmethylsalicylate.. The` yield is. about. 483y g., (56%).. If. desiredx it may bev purifieclby fractionaldistillation, after which it boilsat.173"-1745 C at 9.1mm.,pr.essure.

B25108741; Nn2.5 1.4982'.`

Anaylsis-z Calculatedfor C14H18O4: C, 67.20; H, 7.20.A Found: C,.67.25; H, 7-.74

B. Preparing the 3-n-{batyl-elehydroycoumal-L rai-Heat 9.2 g. of sodium in 200 m1. of; mineral oil to about 250 C.; then add 75 g. of capronylfmethylsalicylate While stirring, and maintain the temperature for about 30 minutes, under reflux,

after such addition is completed.. Decant the) rnineral; oil from the gummy residue Which has been formed; That gummy, residue'solidieson.

cooling. Wash that residue with a low-boiling petroleum fraction, and then stir it into and so far as possible dissolve it in about 800 ml. of Water. Reduce the pH of the solution thus formed to about 13H-7.0, as withhydrochlbriczacid; whereupon an oil separates. Remover that oil by extraction with ether; and separate' the' aqueous.-1ayer,,andacidify it to aboutpH 1.5. On this lastv acidification the desired 3`nbutyl4hy= droxycoumarin crysta'llizest out. Illie yield. is about 23.2 gf.: (26%)..

It may. beprepared When it; is: recrystallizedlfi 11 from ethyl alcohol and water, its melting point is about l58.5l.59.5 C.

Analysis: Calculated for C13H14O3: C, 71.56; H, 6.42. Found: C, 71.81; H, 6.48.

Our overall reaction is as follows:

A. Preparing n heptoylmethylsalicylate-To 20 prepare 3-n-amyl-4-hydroxycoumarin, we use nheptoylmethylsalicylate (n-heptoylsalicylic acid methyl ester) as a reactant. It may be prepared as follows: Reflux 100 g. of heptoyl chloride and 103 g. of methylsalicylate for about 2 hours, and 25 then fractionally distill. Collect the fraction boiling between 173-179 C. at 7 mm. pressure. This is the desired n-heptoylmethylsalicylate. The yield is about 129 g. (73%). If desired it may be purified by fractional distillation, after which it boils at 181-182 C. at 9 mm. pressure.

Analysis: Calculated for C15H20O4; C, 68.18; H, 7.50. Found: C, 68.31; H, 7.86.

B. Preparing 3-fn-amyZ-si-hydroycoumarin- Heat 4.4 g. of sodium in 100 ml. of mineral oil to about 250 C., and add 50 g. of n-heptoylmethylsalicylate while stirring vigorously. Maintain the 250 temperature, under reux, for about 40 or minutes after the addition is complete. Decant the mineral oil to separate it from the gummy residue which has formed; and wash that gummy residue with a low-boiling petroleum fraction, and then stir it into and so far as possible dissolve it in about 800 ml. of water. the pH to about pH 7.5, as by adding hydrochloric acid; whereupon a gummy precipitate forms. Remove that gurnmy precipitate, as by extraction with ether; and then separate the aqueous phase, and acidify it to about pH 1.5, as with hydrochloric acid. The desired 3-namyl-4-hydroxycoumarin crystallizes out during this last acidification. The yield is about 13.4 g. (30%). When recrystallized from ethyl alcohol and Water, its melting point is about IS7-139 C. 5

Analysis: Calculated for 0141-116031 C, 72.41; H, 6.70. Found: C, 72.22; H, 6.91.

Our overall reaction is -as follows:

Example 11.-3 hexadecyl-4-hydr0ycoumarin A. Preparing stearg/ZmethyZsalicylate.-To prepare 3-hexadecyl-4-hydroxycoumarin we use 75 Reduce O eo n CHaOH 12 stearylmethylsalicylate (stearylsalicylic a c i d methyl ester) as a reactant. It may be prepared as follows: Heat g. of stearic acid and 74 g. of phosphorus pentachloride on a steam bath for about 30 minutes, continue the heating under vacuum for 30 minutes longer in a dry nitrogen stream at C., and then, while the mixture is still hot, add 54 g. of methyl salicylate and heat the mixture on a steam bath until the evolution of hydrochloric acid gas ceases, which usually takes about 3 hours. This yields a dark liquid. Fractionally distill that dark liquid, and collect the fraction which boils at 22S-230 C. at 0.05 mm. pressure. The clear distillate solidii'les on cooling. It is the desired stearylmethylsalicylate, which melts at 41-43 C. The yield is about 70 g. (47%).

Analysis: Calculated for C2eH42O4: C, 74.83; H, 10.10. Found: C, 74.81; H, 10.10.

B. Preparing 3-headecyl 4 hydroycoumarin-Heat 2.2 g. of sodium in 100 ml. of mineral oil to about 225 C., and then add 40 g. of stearylmethylsalicylate while stirring vigorously. Maintain the temperature of about 225 C., under reflux, for about 40 or 45 minutes after the addition is complete. Then decant the mineral oil from the heavy syrup which has been formed; and wash that syrup with a low-boiling petroleum fraction, and then stir it into and so far as possible dissolve it in about 600 ml. of water. Shake Iout small portions of the solution thus formed with large amounts of ether; and separate the aqueous layers, and combine them. Then acidify the combined aqueous layer, as with hydrochloric acid, to about pH 1.5. The desired 3-hexadecyl-4-hydroxycoumarin crystallizes out during this acidification. The yield is about 7.6 g. (21%). After recrystallization from petroleum ether its melting point is 96-97" C.

Analysis: Calculated for CzsHasOs: C, 77.16; H, 10.14. Found: C, 77.35; H, 9.77.

Our overall reaction is as follows:

Example 12.-3-phenyl-4hydroxycoumarin A. Preparing a toluylmethylsalzcylate. -To prepare 3phenyl-4-hydroxycoumarin, we use atoluylmethylsalicylate (a toluylsalicylic acid methyl ester) as a reactant. It may be prepared as follows: Reux 470 g. of phenylacetic acid and 720 g. of thionyl chloride until evolution of hydrochloric acid gas ceases. Then fractionally distill the resultant product, and collect the fraction which boils at 103-104 C. at 25 mm. pressure. This fraction is phenylacetyl chloride. The yield is about 487 g. (64%). To 382 g. of this phenylacetyl chloride add 382 g. of methylsalicylate; and heat the mixture at 180 C. until evolution of hydrochloric acid gas ceases. Then slowly add the product, with vigorous stirring, to 6 liters of cold water, which desirably contains a liberal amount of seed crystals from a previous run. Allow the mixture to stand about 3 hours, and then recover the solid matter by filtration, wash it with water, and recrystallize it from ethyl alcohol. It is the desired a-toluylmethylsalicylate, which melts at about 59-60 C. The yield is about 428 g. (63%). Pauly and Lockemann 13.'` (Berichte, vol. 48,p.,28.et seq.) `reported the melting point of their phenylacetylsalicylic acid methyl'esteras above. 509:0.;

B. Preparing 3 phenyl-4-hydroxycoumarin.f Heat 4.0 g..,of-,so.dium in.200,--m1.,of` mineral oil to about 240 C., and then add about 45 g. of atoluylmethylsalicylate while maintaining vigorous stirring. Maintainthetemperature under reiiux for 40 to 45 minutes after such addition is complete. Then decant the mineral oil from the viscous syrup which has formed; and wash that syrup with a low-boiling petroleum fraction, and dissolve it in about 600 ml. of water. Acidify the solution thus obtained to about pH 6.5, as with hydrochloric acid; and remove the oily precipitate formed on that acidification by shaking it out with ether. Separate the aqueous layer, and acidify it to pH 1.5, as with hydrochloric acid. The desired 3-phenyl-4-hydroxycoumarin crystallizes out during this acidification. The yield is about 10.0 g. When recrystallized from ethyl alcohol and Water, the melting point is about 234-235 C. Pauly and Lockemann (Berichte, vol. 48, p. 28 et seq.) report a melting point of 236 C. for the 3phenyl4hydroxy coumarin prepared by them. The reaction by which it is formed is the same as that given in Equation 4 above, save that it is carried out at a very considerably higher temperature and there are few if any side-reaction products contaminating the 3-phenyl-4-hydroxycoumarin.

Example 13.-3-beneyZ-el-hydrozrycoumarin A. Preparing ,8 phenylpropionylmethylsalieylata-To prepare 3-benzyl-Ll-hydroxycoumarin, We use phenylpropionylmethylsalicylate phenylpropionylsalicylic acid methyl ester) as a rectant. It may be prepared as follows: Reflux 30 g. of hydrocinnamic acid and 48 g. of thionyl chloride for about 3 hours. Remove the excess thionyl chloride, as by reducing the pressure. To the remaining acid chloride add 30.4 g. of methyl salicylate, and reflux the mixture for about one hour. Then fractionally distill the dark viscous liquid which has resulted from that refluxing, and collect the fraction boiling at 197-201 C. at 5 mm. pressure. It is the desired -phenylpropionylmethylsalicylate. The yield is about 42 g. (74%).

D25 1.1768. ND25 1.5521.

Analysis: Calculated for Cir/H1604: C, 71.83; H, 5.63. Found: C, 71.88; H, 5.60.

B. Preparing 3-benzyl-4-hydroycoumarn- Heat 2.3 g. of sodium in 100 ml. of mineral oil to about 235 C., and then add about 28.4 of phenylpropionylmethylsalicylate, While stirring vigorously. Maintain the 235 temperature, under reflux, for about half an hour after the addition is complete. Then decant the mineral oil from the gummy residue which has formed; and Wash that gummy residue with a low-boiling petroleum fraction, and then stir it into and so far as possible dissolve it in about 500 ml. of water. Then add acid, conveniently hydrochloric or sulfurie acid, to produce about pH 7.0; extract with ether; and separate the aqueous phase. Acidify that aqueous phase to about pH 1.5. During that acidification the desired 3-benZyl4-hy droxycoumarin crystallizes out. The yield is about 5.5 g. (22%). When recrystallized from 95% ethyl alcohol, its melting point is about 202-205 C. This is the same melting point reported by Heilbron and Hill (Jour. Chem. Soc., vol. II, p. 1705 (1927) for the 3-benZyl-4-hydroxy-coumarin prepared by them from the acid 1:4.. cmorideeQf-iaecty1sa1cv1fa0d anfi-.the diethylester of sodio-benZyl-malonic acid--ar method., wholly different from ours.

Ouaoverall .reaction is.as follows;

We have discovered that al1 these 4hydroxy coumarins have anti-coagulant properties, on either oral or intravenous administration. Most of them, and most of the acylsalicylic acid esters from which they are made, are new with us.

We claim as our invention: 1. The process of producing 4-hydroxycou marins, which consists in condensing with an alkali metal in an inert high-boiling hydrocarbon which boils at not less than 260 C. and with which the initial acyl salicylic acid ester and the alkali metal and the final 4-hydroxycoumarin do not react, a compound of the general formula in which R. represents a member of the class consisting of hydrogen and monovalent hydrocarbon groups, and R represents a monovalent hydrocarbon group.

2. The process of producing 4-hydroxycoumarin, which consists in condensing with an alkali metal in an inert high-boiling hydrocarbon Which boils at not less than 260 C. and with which the initial acyl salicylic acid ester and the alkali metal and the iinal 4-hydroxycoumarin do not react, a compound of the general formula in which R represents a monovalent hydrocarbon group.

3. The process of producing 4hydroxycou marin, which consists in condensing acetyl methylsalicylate with an alkali metal in an inert high-boiling hydrocarbon Iwhich boils at not less than 260 C. and with which the initial acyl salicylic acid ester and the alkali metal and the nal 4-hydroxycoumarin do not react.

4. The process of producing 4-hydroxycoumarins as set forth in claim 1, in which the alkali metal is sodium.

5. The process of producing 4-hydroxycoumarin as set forth in claim 2, in which the a1- kali metal is sodium.

6. The process of producing 4-hydroxycoumarin as set forth in claim 3, in which the a1- kali metal is sodium.

'7. The process of producing 4-hydroxycou- M marins as set forth in claim 1 in which the REFERENCES CITED condensation is done between 220 and 230 C- The following references are of record in the 8. 'Ihe process of producing 4-hydroXycoufile 0f llS EPS/tenti marin as set forth in claim 2, in which the con- 5 densation is done between 220` and 280 C. A UNITED STATES PATENTS 9. The process of producing 4-hydroxycou- Number Name Date marin as set forth in claim 3, in which the con- 2:349,'765 Shelton May 23J 1944 densation is done between 220 and 280 C.

MARK A. STAHMANN. 10 KARL PAUL LINK. 

